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US20090176766A1 - Imidazolidinone and imidazolidinethione derivatives - Google Patents

Imidazolidinone and imidazolidinethione derivatives Download PDF

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US20090176766A1
US20090176766A1 US12/348,480 US34848009A US2009176766A1 US 20090176766 A1 US20090176766 A1 US 20090176766A1 US 34848009 A US34848009 A US 34848009A US 2009176766 A1 US2009176766 A1 US 2009176766A1
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compound
phenyl
aryl
heteroaryl
cycloalkyl
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Jyh-Haur Chern
Tsu-An Hsu
Iou-Jiun Kang
Li-Wen Wang
Chung-Chi Lee
Yen-Chun Lee
Yen-Shian Wu
Sheng-Ju Hsu
Yueh Andrew Yueh
Yu-Sheng Chao
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National Health Research Institutes
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/34—Ethylene-urea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/42—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • HCV infection is estimated to affect 170 million individuals worldwide. This disease is primarily transmitted through contaminated blood products. Although its spread has been slowed as a result of improvement in blood screening in many countries, it remains the leading cause of liver disease-related deaths in the world. For example, it causes about 10,000 deaths annually in the U.S. alone. In the absence of effective therapies, the death rate is expected to triple over the next 2 decades. Current treatments based on interferon-alpha have low success rates, particularly for genotype-1 infections predominant in Europe, Japan, and the U.S. Also, they are expensive and poorly received by patients. Thus, there is a need to develop better therapeutic agents for treating HCV infection.
  • This invention is based on the discovery that certain imidazolidinone and imidazolinethione compounds are effective in treating hepatitis C virus infection.
  • this invention relates to a compound of formula (I):
  • each of R 1 , R 2 , and R 3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; or R 1 and R 2 , together with the nitrogen atom to which they are bonded, are heterocycloalkyl; or R 2 and R 3 , together with the two nitrogen atoms to which they are bonded and the carbon atom bonded to both of the two nitrogen atoms, are heterocycloalkyl; each of A 1 and A 2 , independently, is aryl or heteroaryl; each of X and Y, independently, is O, S, SO, SO 2 , N(R 3 ), C(R a R b ), C(O), C(O)O, C(O)NR a , NR a C(O)NR b , NR a C(S)NR b
  • a 1 can be 1,3-phenylene
  • a 2 can be phenyl, pyridyl, or naphthyl optionally substituted with halo, alkoxy, aryloxy, alkyl, cycloalkyl, aryl, or heteroaryl
  • each of R 1 , R 2 , and R 3 can be H
  • Y can be 1,4-phenylene and y can be 0 or 1.
  • imidazolidinone and imidazolinethione compounds includes those in which A 1 is 1,3-phenylene and A 2 is phenyl, pyridyl, or naphthyl optionally substituted with halo, alkoxy, aryloxy, alkyl, cycloalkyl, aryl, or heteroaryl.
  • each of R 1 , R 2 , and R 3 can be H.
  • alkyl refers to a straight or branched monovalent hydrocarbon containing 1-20 carbon atoms (e.g., C 1 -C 10 ). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.
  • alkylene refers to a straight or branched bivalent hydrocarbon, containing 1-20 carbon atoms (e.g., C 1 -C 10 ). Examples of alkylene include, but are not limited to, methylene and ethylene.
  • alkenyl and alkenylene respectively refer to a straight or branched monovalent and bivalent hydrocarbon containing 2-20 carbon atoms (e.g., C 2 -C 10 ) and one or more double bonds.
  • alkenyl and alkenylene include, but are not limited to, ethenyl, propenyl, propenylene, allyl, and 1,4-butadienyl.
  • alkynyl and alkynylene respectively refer to a straight or branched monovalent and bivalent hydrocarbon containing 2-20 carbon atoms (e.g., C 2 -C 10 ) and one or more triple bonds.
  • alkynyl and alkynylene examples include, but are not limited to, ethynyl, 1-propynyl, 1- and 2-butynyl, and 1-methyl-2-butynyl.
  • alkoxy refers to an —O-alkyl radical. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
  • cycloalkyl and “cycloalkylene” respectively refer to a monovalent and a bivalent saturated hydrocarbon ring system having 3 to 30 carbon atoms (e.g., C 3 -C 12 ).
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • cycloalkenyl and cycloalkenylene respectively refer to a monovalent and a bivalent non-aromatic hydrocarbon ring system having 3 to 30 carbons (e.g., C 3 -C 12 ) and one or more double bonds. Examples include cyclopentanyl, cyclohexanyl, and cycloheptanyl.
  • heterocycloalkyl and heterocycloalkylene respectively refer to a monovalent and a bivalent nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se).
  • heterocycloalkyl and heterocycloalkylene groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.
  • heterocycloalkenyl refers to a monovalent nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se) and one or more double bonds.
  • heterocycloalkenylene refers to a bivalent nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se) and one or more double bonds.
  • aryl refers to a monovalent 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • arylene refers to a bivalent 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system.
  • aryloxyl refers to an —O-aryl.
  • heteroaryl refers to a monvalent aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se).
  • heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl.
  • heteroarylene refers to a bivalent aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se).
  • Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, cycloalkenylene, heterocycloalkenylene, arylene, and heteroarylene mentioned above include both substituted and unsubstituted moieties.
  • cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkylene, heterocycloalkylene, cycloalkenylene, heterocycloalkenylene, aryl, and heteroaryl include, but are not limited to, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkenyl, C 1 -C 20 heterocycloalkyl, C 1 -C 20 heterocycloalkenyl, C 1 -C 10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C 1 -C 10 alkylamino, C 1 -C 20 dialkylamino, arylamino, diarylamino, hydroxyl, halo, thio, C 1 -C 10 alkylthi
  • alkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene include all of the above-recited substituents except C 1 -C 10 alkyl.
  • Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl can also be fused with each other.
  • this invention relates to a method of treating HCV infection by administering to a subject infected with HCV an effective amount of one or more of the imidazolidinone and imidazolinethione compounds described above.
  • compositions containing one or more of the above-described imidazolidinone and imidazolinethione compounds for use in treating HCV infection, as well as this therapeutic use and use of the compounds for the manufacture of a medicament for treating HCV infection.
  • the imidazolidinone and imidazolinethione compounds of this invention can be prepared by conventional chemical transformations (including protecting group methodologies), e.g., those described in R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995) and subsequent editions thereof.
  • Schemes 1-3 below show transformations for synthesizing compounds of this invention.
  • a typical method of preparing the imidazolidinone compounds 15 of the present invention is shown in Scheme 2.
  • the 4-aminobutan-1-ol is coupled with aryl isocyanate 9 to afford the corresponding urea intermediate 10.
  • Tosylation of hydroxyl compound 10 with tosyl chloride in pyridine at room temperature affords the corresponding tosylate 11.
  • Subsequent intramolecular cyclization of the intermediate 11 by treatment with sodium hydride in the THF/DMF cosolvent system at room temperature results in the formation of cyclic urea 12.
  • Nucleophilic substitution of the cyclic urea 12 with the bromo compound 2 in the presence of sodium hydride in DMF gives compound 13.
  • An imidazolidinone or imidazolinethione compound thus synthesized can be further purified by flash column chromatography, high performance liquid chromatography, crystallization, or any other suitable methods.
  • a pharmaceutical composition that contains an effective amount of at least one of the imidazolidinone and imidazolinethione compounds of this invention and a pharmaceutically acceptable carrier, and (2) a method for treating HCV infection by administering to a subject in need of this treatment an effective amount of such an imidazolidinone or imidazolinethione compound.
  • the term “treating” refers to administering an imidazolidinone or imidazolinethione compound to a subject that has HCV infection, or has a symptom of HCV infection, or has a predisposition toward HCV infection, with the purpose to prevent, cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the HCV infection, the symptoms of the HCV infection, or the predisposition toward the HCV infection.
  • an effective amount refers to the amount of the active agent that is required to confer the intended therapeutic effect in the subject. Effective amounts may vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and the possibility of co-usage with other agents.
  • the above-described pharmaceutical composition can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.
  • a sterile injectable composition e.g., a sterile injectable aqueous or oleaginous suspension
  • a sterile injectable preparation can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides).
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
  • Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
  • a composition for oral administration can be any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents, such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.
  • a nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation.
  • An imidazolidinone or imidazolinethione compound-containing composition can also be administered in the form of suppositories for rectal administration.
  • the carrier in the pharmaceutical composition must be “acceptable” in the sense of being compatible with the active ingredient of the formulation (and preferably, capable of stabilizing it) and not deleterious to the subject to be treated.
  • solubilizing agents such as cyclodextrins, which form more soluble complexes with the imidazolidinone or imidazolinethione compounds, can be utilized as pharmaceutical carriers for delivery of the active compounds.
  • examples of other carriers include colloidal silicon dioxide, magnesium stearate, sodium lauryl sulfate, and D&C Yellow #10.
  • Suitable in vitro assays can be used to preliminarily evaluate the efficacy of the imidazolidinone or imidazolinethione compounds of this invention in inhibiting HCV replication.
  • the compounds can further be examined for their efficacy in treating HCV infection.
  • a compound can be administered to an animal (e.g., a mouse model) infected with HCV and its therapeutic effects are then assessed. Based on the results, an appropriate dosage range and administration route can also be determined.
  • Ava5-EG( ⁇ 4AB)SEAP a reporter-based cell line
  • Ava5-EG( ⁇ 4AB)SEAP cells were cultured in a medium containing 500 ⁇ g/mL G418 (geneticin) and 10 ⁇ g/mL blasticidin in a 5% CO 2 incubator. G418 and blasticidin were purchased from Invitrogen (Carlsbad, Calif.).
  • the cells were seeded in a 96-well plate (5 ⁇ 10 3 cells/100 ⁇ L-well) and incubated at 37° C. for 24 hours. They were then treated with a solution of a test compound in DMSO at various concentrations. After 48 hours, the culture medium in each well was replaced with a fresh medium containing the test compound at the same concentrations to remove secreted alkaline phosphatase accumulated in the culture medium, if any. The cells were cultured for additional 24 hours. The culture medium was then collected and tested for SEAP activity using a Phospha-Light assay kit (Tropix, Foster, Calif., USA). Compounds in Examples 1-18 were tested in this assay.
  • 17 of the test compounds showed EC 50 values (i.e., the concentration of a test compound at which 50% HCV replication is inhibited) lower than 1.5 ⁇ M. 14 of them showed even lower EC 50 values, e.g., lower than 0.5 ⁇ M.
  • Viability of cells after treatment was determined by the MTS assay described in Cory et al., Cancer Commun. 3:207-12 (1991). Briefly, Ava5-EG( ⁇ 4AB)SEAP cells were treated with a test compound as described above. After 48 hours, each culture medium was replaced with a fresh medium containing the test compound at the same concentration. The cells were cultured for additional 24 hours.

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Abstract

Imidazolidinone and imidazolinethione compounds of formula (I):
Figure US20090176766A1-20090709-C00001
wherein R1, R2, R3, A1, A2, X, Y, Z, m, n, p, x, and y are defined herein. Also disclosed is a method of treating hepatitis C virus infection with these compounds.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application claims priority to U.S. Provisional Application Ser. No. 61/019,663 filed Jan. 8, 2008. The contents of the prior application are hereby incorporated by reference in their entireties.
    • BACKGROUND
  • Hepatitis C virus (HCV) infection is estimated to affect 170 million individuals worldwide. This disease is primarily transmitted through contaminated blood products. Although its spread has been slowed as a result of improvement in blood screening in many countries, it remains the leading cause of liver disease-related deaths in the world. For example, it causes about 10,000 deaths annually in the U.S. alone. In the absence of effective therapies, the death rate is expected to triple over the next 2 decades. Current treatments based on interferon-alpha have low success rates, particularly for genotype-1 infections predominant in Europe, Japan, and the U.S. Also, they are expensive and poorly received by patients. Thus, there is a need to develop better therapeutic agents for treating HCV infection.
    • SUMMARY
  • This invention is based on the discovery that certain imidazolidinone and imidazolinethione compounds are effective in treating hepatitis C virus infection.
  • In one aspect, this invention relates to a compound of formula (I):
  • Figure US20090176766A1-20090709-C00002
  • In formula (I), each of R1, R2, and R3, independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; or R1 and R2, together with the nitrogen atom to which they are bonded, are heterocycloalkyl; or R2 and R3, together with the two nitrogen atoms to which they are bonded and the carbon atom bonded to both of the two nitrogen atoms, are heterocycloalkyl; each of A1 and A2, independently, is aryl or heteroaryl; each of X and Y, independently, is O, S, SO, SO2, N(R3), C(RaRb), C(O), C(O)O, C(O)NRa, NRaC(O)NRb, NRaC(S)NRb, NRaC(O)O, SO2NRa, alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, cycloalkenylene, heterocycloalkenylene, arylene, or heteroarylene, in which each of Ra and Rb, independently, is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Z is O or S; each of m and n, independently, is 0, 1, 2, 3, 4, or 5; p is 1, 2, or 3; and each of x and y, independently, is 0 or 1.
  • One subset of the above-described imidazolidinone and imidazolinethione compounds includes those in which X is O and x is 1. In these compounds, A1 can be 1,3-phenylene; A2 can be phenyl, pyridyl, or naphthyl optionally substituted with halo, alkoxy, aryloxy, alkyl, cycloalkyl, aryl, or heteroaryl; each of R1, R2, and R3 can be H; or Y can be 1,4-phenylene and y can be 0 or 1.
  • Another subset of the imidazolidinone and imidazolinethione compounds includes those in which A1 is 1,3-phenylene and A2 is phenyl, pyridyl, or naphthyl optionally substituted with halo, alkoxy, aryloxy, alkyl, cycloalkyl, aryl, or heteroaryl. In these compounds, each of R1, R2, and R3 can be H.
  • The term “alkyl” refers to a straight or branched monovalent hydrocarbon containing 1-20 carbon atoms (e.g., C1-C10). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. The term “alkylene” refers to a straight or branched bivalent hydrocarbon, containing 1-20 carbon atoms (e.g., C1-C10). Examples of alkylene include, but are not limited to, methylene and ethylene. The terms “alkenyl” and “alkenylene” respectively refer to a straight or branched monovalent and bivalent hydrocarbon containing 2-20 carbon atoms (e.g., C2-C10) and one or more double bonds. Examples of alkenyl and alkenylene include, but are not limited to, ethenyl, propenyl, propenylene, allyl, and 1,4-butadienyl. The terms “alkynyl” and “alkynylene” respectively refer to a straight or branched monovalent and bivalent hydrocarbon containing 2-20 carbon atoms (e.g., C2-C10) and one or more triple bonds. Examples of alkynyl and alkynylene include, but are not limited to, ethynyl, 1-propynyl, 1- and 2-butynyl, and 1-methyl-2-butynyl. The term “alkoxy” refers to an —O-alkyl radical. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
  • The terms “cycloalkyl” and “cycloalkylene” respectively refer to a monovalent and a bivalent saturated hydrocarbon ring system having 3 to 30 carbon atoms (e.g., C3-C12). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The terms “cycloalkenyl” and “cycloalkenylene” respectively refer to a monovalent and a bivalent non-aromatic hydrocarbon ring system having 3 to 30 carbons (e.g., C3-C12) and one or more double bonds. Examples include cyclopentanyl, cyclohexanyl, and cycloheptanyl. The terms “heterocycloalkyl” and “heterocycloalkylene” respectively refer to a monovalent and a bivalent nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se). Examples of heterocycloalkyl and heterocycloalkylene groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl. The term “heterocycloalkenyl” refers to a monovalent nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se) and one or more double bonds. The term “heterocycloalkenylene” refers to a bivalent nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se) and one or more double bonds.
  • The term “aryl” refers to a monovalent 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The term “arylene” refers to a bivalent 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system. The term “aryloxyl” refers to an —O-aryl. The term “heteroaryl” refers to a monvalent aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se). Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl. The term “heteroarylene” refers to a bivalent aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se).
  • Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, cycloalkenylene, heterocycloalkenylene, arylene, and heteroarylene mentioned above include both substituted and unsubstituted moieties. Possible substituents on cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkylene, heterocycloalkylene, cycloalkenylene, heterocycloalkenylene, aryl, and heteroaryl include, but are not limited to, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C10 alkylamino, C1-C20 dialkylamino, arylamino, diarylamino, hydroxyl, halo, thio, C1-C10 alkylthio, arylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, mercapto, amido, thioureido, thiocyanato, sulfonamido, guanidine, ureido, cyano, nitro, acyl, thioacyl, acyloxy, carbamido, carbamyl, carboxyl, and carboxylic ester. On the other hand, possible substituents on alkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene include all of the above-recited substituents except C1-C10 alkyl. Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl can also be fused with each other.
  • In still another aspect, this invention relates to a method of treating HCV infection by administering to a subject infected with HCV an effective amount of one or more of the imidazolidinone and imidazolinethione compounds described above.
  • Also within the scope of this invention is a pharmaceutical composition containing one or more of the above-described imidazolidinone and imidazolinethione compounds for use in treating HCV infection, as well as this therapeutic use and use of the compounds for the manufacture of a medicament for treating HCV infection.
  • The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and the claims.
    • DETAILED DESCRIPTION
  • Shown in the table below are 26 exemplary compounds of this invention:
  • Structure Name M + 1
    1
    Figure US20090176766A1-20090709-C00003
         		(3-{5-[3-(4- Chloro-phenyl)- 2-oxo- imidazolidin-1- yl]-pentyloxy}- phenyl)-thiourea 433
    2
    Figure US20090176766A1-20090709-C00004
         		(3-{5-[3-(4- Chloro-phenyl)- 2-thioxo- imidazolidin-1- yl]-pentyloxy}- phenyl)-thiourea 449
    3
    Figure US20090176766A1-20090709-C00005
         		{3-[5-(3- Naphthalen-1-yl- 2-oxo- imidazolidin-1- yl)-pentyloxy]- phenyl}-thiourea 449
    4
    Figure US20090176766A1-20090709-C00006
         		{3-[5-(3- Naphthalen-1-yl- 2-thioxo- imidazolidin-1- yl)-pentyloxy]- phenyl}-thiourea 465
    5
    Figure US20090176766A1-20090709-C00007
         		(3-{7-[3-(4- Chloro-phenyl)- 2-oxo- imidazolidin-1- yl]-heptyloxy}- phenyl)-thiourea 461
    6
    Figure US20090176766A1-20090709-C00008
         		(3-{7-[3-(4- Chloro-phenyl)- 2-thioxo- imidazolidin-1- yl]-heptyloxy}- phenyl)-thiourea 477
    7
    Figure US20090176766A1-20090709-C00009
         		(3-{5-[2-Oxo-3- (4-phenoxy- phenyl)- imidazolidin-1- yl]-pentyloxy}- phenyl)-thiourea 491
    8
    Figure US20090176766A1-20090709-C00010
         		(3-{5-[3-(4- Phenoxy-phenyl)- 2-thioxo- imidazolidin-1- yl]-pentyloxy}- phenyl)-thiourea 507
    9
    Figure US20090176766A1-20090709-C00011
         		{3-[5-(2-Oxo-3- pyridin-3-yl- imidazolidin-1- yl)-pentyloxy]- phenyl}-thiourea 400
    10
    Figure US20090176766A1-20090709-C00012
         		{3-[5-(3-Pyridin- 3-yl-2-thioxo- imidazolidin-1- yl)-pentyloxy]- phenyl}-thiourea 416
    11
    Figure US20090176766A1-20090709-C00013
         		(3-{5-[3-(4- Chloro-phenyl)- 2-oxo-tetrahydro- pyrimidin-1-yl]- pentyloxy}- phenyl)-thiourea 447
    12
    Figure US20090176766A1-20090709-C00014
         		(3-{5-[3-(4- Chloro-phenyl)- 2-thioxo- tetrahydro- pyrimidin-1-yl]- pentyloxy}- phenyl)-thiourea 463
    13
    Figure US20090176766A1-20090709-C00015
         		(3-{4-[3-(4- Chloro-phenyl)- 2-oxo- imidazolidin-1- ylmethyl]- benzyloxy}- phenyl)-thiourea 467
    14
    Figure US20090176766A1-20090709-C00016
         		(3-{4-[3-(4- Chloro-phenyl)- 2-thioxo- imidazolidin-1- ylmethyl]- benzyloxy}- phenyl)-thiourea 483
    15
    Figure US20090176766A1-20090709-C00017
         		(3-{5-[3-(2,4- Dichloro- phenyl)-2-oxo- imidazolidin-1- yl]-pentyloxy}- phenyl)-thiourea 467
    16
    Figure US20090176766A1-20090709-C00018
         		(3-{5-[3-(2,4- Dichloro- phenyl)-2-thioxo- imidazolidin-1- yl]-pentyloxy}- phenyl)-thiourea 483
    17
    Figure US20090176766A1-20090709-C00019
         		(3-{5-[3-(3,4- Dichloro- phenyl)-2-oxo- imidazolidin-1- yl]-pentyloxy}- phenyl)-thiourea 467
    18
    Figure US20090176766A1-20090709-C00020
         		(3-{5-[3-(3,4- Dichloro- phenyl)-2-thioxo- imidazolidin-1- yl]-pentyloxy}- phenyl)-thiourea 483
    19
    Figure US20090176766A1-20090709-C00021
         		(3-{5-[3-(4- Benzyl-phenyl)- 2-oxo- imidazolidin-1- yl]-pentyloxy}- phenyl)-thiourea 489
    20
    Figure US20090176766A1-20090709-C00022
         		(3-{5-[3-(4- Benzyl-phenyl)- 2-thioxo- imidazolidin-1- yl]-pentyloxy}- phenyl)-thiourea 505
    21
    Figure US20090176766A1-20090709-C00023
         		(3-{5-[3-(4- Cyclohexyl- phenyl)-2-oxo- imidazolidin-1- yl]-pentyloxy}- phenyl)-thiourea 481
    22
    Figure US20090176766A1-20090709-C00024
         		3-{5-[3-(4- Cyclohexyl- phenyl)-2-thioxo- imidazolidin-1- yl]-pentyloxy}- phenyl)-thiourea 497
    23
    Figure US20090176766A1-20090709-C00025
         		(3-{5-[3-(4- Chloro-phenyl)- 2-oxo- [1,3]diazepan-1- yl]-pentyloxy}- phenyl)-thiourea 461
    24
    Figure US20090176766A1-20090709-C00026
         		(3-{5-[3-(4- Chloro-phenyl)- 2-thioxo- [1,3]diazepan-1- yl]-pentyloxy}- phenyl)-thiourea 477
    25
    Figure US20090176766A1-20090709-C00027
         		{3-[5-(3- Biphenyl-2-yl-2- oxo-imidazolidin- 1-yl)-pentyloxy]- phenyl}-thiourea 475
    26
    Figure US20090176766A1-20090709-C00028
         		{3-[5-(3- Biphenyl-2-yl-2- thioxo- imidazolidin-1- yl)-pentyloxy]- phenyl}-thiourea 491
  • The imidazolidinone and imidazolinethione compounds of this invention can be prepared by conventional chemical transformations (including protecting group methodologies), e.g., those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. Schemes 1-3 below show transformations for synthesizing compounds of this invention.
  • The route shown in Scheme 1 exemplifies synthesis of the imidazolidinone compounds 8 of the present invention. 1,5-Dibromopentane 1 can first react with the 3-nitrophenol in the presence of potassium carbonate in NMP via a substitution reaction to form an alkoxy-containing compound 2. The aryl amine compound 3 is coupled with chloroalkyl isocyanate to afford the corresponding urea intermediate 4. Subsequent intramolecular cyclization of the intermediate 4 by treatment with sodium hydride in the THF/DMF cosolvent system at room temperature results in the formation of cyclic urea 5. Nucleophilic substitution of the cyclic urea 5 with the bromo compound 2 in the presence of sodium hydride in DMF affords compound 6. Subsequent reduction of the nitro group of compound 6 with tin chloride affords the corresponding aryl amine 7. Reaction of the aryl amine 7 with thiocarbonyl diimidazole (TCDI) followed by treatment with 25% aqueous ammonia solution affords the desired imidazolidinone compounds 8.
  • Figure US20090176766A1-20090709-C00029
  • A typical method of preparing the imidazolidinone compounds 15 of the present invention is shown in Scheme 2. The 4-aminobutan-1-ol is coupled with aryl isocyanate 9 to afford the corresponding urea intermediate 10. Tosylation of hydroxyl compound 10 with tosyl chloride in pyridine at room temperature affords the corresponding tosylate 11. Subsequent intramolecular cyclization of the intermediate 11 by treatment with sodium hydride in the THF/DMF cosolvent system at room temperature results in the formation of cyclic urea 12. Nucleophilic substitution of the cyclic urea 12 with the bromo compound 2 in the presence of sodium hydride in DMF gives compound 13. Subsequent reduction of the nitro group of compound 13 with tin chloride affords the corresponding aryl amine 14. Reaction of the aryl amine 14 with thiocarbonyl diimidazole (TCDI) followed by treatment with 25% aqueous ammonia solution gives the desired imidazolidinone compounds 15.
  • Figure US20090176766A1-20090709-C00030
  • The route shown in Scheme 3 exemplifies synthesis of the imidazolinethione compounds 18 of this invention. The nitro compound (6 or 13) is reacted with phosphorus pentasulfide to afford the corresponding imidazolidinethione compound 16. Subsequent reduction of the imidazolidinethione compound 16 with tin chloride gives the aryl amine 17. Reaction of the aryl amine 17 with thiocarbonyl diimidazole (TCDI) followed by treatment with 25% aqueous ammonia solution affords the desired imidazolinethione compounds 18.
  • Figure US20090176766A1-20090709-C00031
  • An imidazolidinone or imidazolinethione compound thus synthesized can be further purified by flash column chromatography, high performance liquid chromatography, crystallization, or any other suitable methods.
  • Also within the scope of this invention are (1) a pharmaceutical composition that contains an effective amount of at least one of the imidazolidinone and imidazolinethione compounds of this invention and a pharmaceutically acceptable carrier, and (2) a method for treating HCV infection by administering to a subject in need of this treatment an effective amount of such an imidazolidinone or imidazolinethione compound.
  • As used herein, the term “treating” refers to administering an imidazolidinone or imidazolinethione compound to a subject that has HCV infection, or has a symptom of HCV infection, or has a predisposition toward HCV infection, with the purpose to prevent, cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the HCV infection, the symptoms of the HCV infection, or the predisposition toward the HCV infection. The term “an effective amount” refers to the amount of the active agent that is required to confer the intended therapeutic effect in the subject. Effective amounts may vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and the possibility of co-usage with other agents.
  • To practice the method of this invention, the above-described pharmaceutical composition can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.
  • A sterile injectable composition, e.g., a sterile injectable aqueous or oleaginous suspension, can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides). Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
  • A composition for oral administration can be any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added. A nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation. An imidazolidinone or imidazolinethione compound-containing composition can also be administered in the form of suppositories for rectal administration.
  • The carrier in the pharmaceutical composition must be “acceptable” in the sense of being compatible with the active ingredient of the formulation (and preferably, capable of stabilizing it) and not deleterious to the subject to be treated. For example, one or more solubilizing agents such as cyclodextrins, which form more soluble complexes with the imidazolidinone or imidazolinethione compounds, can be utilized as pharmaceutical carriers for delivery of the active compounds. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, sodium lauryl sulfate, and D&C Yellow #10.
  • Suitable in vitro assays can be used to preliminarily evaluate the efficacy of the imidazolidinone or imidazolinethione compounds of this invention in inhibiting HCV replication. The compounds can further be examined for their efficacy in treating HCV infection. For example, a compound can be administered to an animal (e.g., a mouse model) infected with HCV and its therapeutic effects are then assessed. Based on the results, an appropriate dosage range and administration route can also be determined.
  • Without further elaboration, it is believed that the above description has adequately enabled the present invention. The following examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All of the publications cited herein are hereby incorporated by reference in their entirety.
    • Example 1 Synthesis of (3-{5-[3-(4-chloro-phenyl)-2-oxo-imidazolidin-1-yl]-pentyloxy}-phenyl)-thiourea (Compound 1)
  • Compound 1 was prepared in a manner similar to that outlined in Scheme 1.
    • Examples 2 Synthesis of (3-{5-[3-(4-chloro-phenyl)-2-thioxo-imidazolidin-1-yl]-pentyloxy}-phenyl)-thiourea (Compound 2)
  • Compound 2 was prepared in a manner similar to that outlined in Scheme 3.
    • Example 3 Synthesis of {3-[5-(3-naphthalen-1-yl-2-oxo-imidazolidin-1-yl)-pentyloxy]-phenyl}-thiourea (Compound 3)
  • Compound 3 was prepared in a manner similar to that outlined in Scheme 1.
    • Example 4 Synthesis of (3-{7-[3-(4-chloro-phenyl)-2-oxo-imidazolidin-1-yl]-heptyloxy}-phenyl)-thiourea (Compound 5)
  • Compound 5 was prepared in a manner similar to that outlined in Scheme 1.
    • Example 5 Synthesis of (3-{5-[2-oxo-3-(4-phenoxy-phenyl)-imidazolidin-1-yl]-pentyloxy}-phenyl)-thiourea (Compound 7)
  • Compound 7 was prepared in a manner similar to that outlined in Scheme 1.
    • Example 6 Synthesis of {3-[5-(2-oxo-3-pyridin-3-yl-imidazolidin-1-yl)-pentyloxy]-phenyl}-thiourea (Compound 9)
  • Compound 9 was prepared in a manner similar to that outlined in Scheme 1.
    • Example 7 Synthesis of (3-{5-[3-(4-chloro-phenyl)-2-oxo-tetrahydro-pyrimidin-1-yl]-pentyloxy}-phenyl)-thiourea (Compound 11)
  • Compound 11 was prepared in a manner similar to that outlined in Scheme 1.
    • Example 8 Synthesis of (3-{4-[3-(4-chloro-phenyl)-2-oxo-imidazolidin-1-ylmethyl]-benzyloxy}-phenyl)-thiourea (Compound 13)
  • Compound 13 was prepared in a manner similar to that outlined in Scheme 1.
    • Example 9 Synthesis of (3-{5-[3-(2,4-dichloro-phenyl)-2-oxo-imidazolidin-1-yl]-pentyloxy}-phenyl)-thiourea (Compound 15)
  • Compound 15 was prepared in a manner similar to that outlined in Scheme 1.
    • Example 10 Synthesis of (3-{5-[3-(2,4-dichloro-phenyl)-2-thioxo-imidazolidin-1-yl]-pentyloxy}-phenyl)-thiourea (Compound 16)
  • Compound 16 was prepared in a manner similar to that outlined in Scheme 3.
    • Example 11 Synthesis of (3-{5-[3-(3,4-dichloro-phenyl)-2-oxo-imidazolidin-1-yl]-pentyloxy}-phenyl)-thiourea (Compound 17)
  • Compound 17 was prepared in a manner similar to that outlined in Scheme 1.
    • Example 12 Synthesis of (3-{5-[3-(3,4-dichloro-phenyl)-2-thioxo-imidazolidin-1-yl]-pentyloxy}-phenyl)-thiourea (Compound 18)
  • Compound 18 was prepared in a manner similar to that outlined in Scheme 3.
    • Example 13 Synthesis of (3-{5-[3-(4-benzyl-phenyl)-2-oxo-imidazolidin-1-yl]-pentyloxy}-phenyl)-thiourea (Compound 19)
  • Compound 19 was prepared in a manner similar to that outlined in Scheme 1.
    • Example 14 Synthesis of (3-{5-[3-(4-cyclohexyl-phenyl)-2-oxo-imidazolidin-1-yl]-pentyloxy}-phenyl)-thiourea (Compound 21)
  • Compound 21 was prepared in a manner similar to that outlined in Scheme 1.
    • Example 15 Synthesis of (3-{5-[3-(4-cyclohexyl-phenyl)-2-thioxo-imidazolidin-1-yl]-pentyloxy}-phenyl)-thiourea (Compound 22)
  • Compound 22 was prepared in a manner similar to that outlined in Scheme 3.
    • Example 16 Synthesis of (3-{5-[3-(4-chloro-phenyl)-2-oxo-[1,3]diazepan-1-yl]-pentyloxy}-phenyl)-thiourea (Compound 23)
  • Compound 23 was prepared in a manner similar to that outlined in Scheme 2.
    • Example 17 Synthesis of {3-[5-(3-biphenyl-2-yl-2-oxo-imidazolidin-1-yl)-pentyloxy]-phenyl}-thiourea (Compound 25)
  • Compound 25 was prepared in a manner similar to that outlined in Scheme 1.
    • Example 18 Synthesis of {3-[5-(3-biphenyl-2-yl-2-thioxo-imidazolidin-1-yl)-pentyloxy]-phenyl}-thiourea (Compound 26)
  • Compound 26 was prepared in a manner similar to that outlined in Scheme 3.
    • Example 19 Inhibiting HCV Replication
  • The inhibitory activity of compounds of this invention against HCV replication was assessed using Ava5-EG(Δ4AB)SEAP, a reporter-based cell line, according to the methods described in Lee et al., Anal. Biochem., 316:162-70 (2003) and Lee et al., J. Virol Methods, 116:27-33 (2004). Briefly, Ava5-EG(Δ4AB)SEAP cells were cultured in a medium containing 500 μg/mL G418 (geneticin) and 10 μg/mL blasticidin in a 5% CO2 incubator. G418 and blasticidin were purchased from Invitrogen (Carlsbad, Calif.). The cells were seeded in a 96-well plate (5×103 cells/100 μL-well) and incubated at 37° C. for 24 hours. They were then treated with a solution of a test compound in DMSO at various concentrations. After 48 hours, the culture medium in each well was replaced with a fresh medium containing the test compound at the same concentrations to remove secreted alkaline phosphatase accumulated in the culture medium, if any. The cells were cultured for additional 24 hours. The culture medium was then collected and tested for SEAP activity using a Phospha-Light assay kit (Tropix, Foster, Calif., USA). Compounds in Examples 1-18 were tested in this assay. Unexpectedly, 17 of the test compounds showed EC50 values (i.e., the concentration of a test compound at which 50% HCV replication is inhibited) lower than 1.5 μM. 14 of them showed even lower EC50 values, e.g., lower than 0.5 μM.
    • Example 20 Cytotoxicity Assay
  • Viability of cells after treatment (see Example 19 above) was determined by the MTS assay described in Cory et al., Cancer Commun. 3:207-12 (1991). Briefly, Ava5-EG(Δ4AB)SEAP cells were treated with a test compound as described above. After 48 hours, each culture medium was replaced with a fresh medium containing the test compound at the same concentration. The cells were cultured for additional 24 hours. To each well was added 100 μl of a solution containing phenol red-free DMEM, [3-(4,5-dimethylthiozol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] (Promega, Madison, Wis.), and phenazine methosulfate (Sigma, St. Louis, Mo.) at a ratio of 80:20:1. The cells were incubated at 37° C. for 1-4 hours in a 5% CO2 incubator. The absorbance at 490 nm in each well was measured. Compounds in Examples 1-18 were tested in this assay. Unexpectedly, all of the test compounds showed CC50 values (i.e., the concentration of a test compound at which 50% of the cells are killed) greater than 10 μM and 7 of them showed CC50 values greater than 50 μM.
    • Other Embodiments
  • All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.
  • From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.

Claims (25)

1. A compound of formula (I):
Figure US20090176766A1-20090709-C00032
wherein
each of R1, R2, and R3, independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; or R1 and R2, together with the nitrogen atom to which they are bonded, are heterocycloalkyl; or R2 and R3, together with the two nitrogen atoms to which they are bonded and the carbon atom bonded to both of the two nitrogen atoms, are heterocycloalkyl;
A1 is arylene or heteroarylene;
A2 is aryl or heteroaryl;
each of X and Y, independently, is O, S, SO, SO2, N(Ra), C(RaRb), C(O), C(O)O, C(O)NRa, NRaC(O)NRb, NRaC(S)NRb, NRaC(O)O, SO2NRa, alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, cycloalkenylene, heterocycloalkenylene, arylene, or heteroarylene, in which each of Ra and Rb, independently, is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Z is O or S;
each of m and n, independently, is 0, 1, 2, 3, 4, or 5;
p is 1, 2, or 3; and
each of x and y, independently, is 0 or 1.
2. The compound of claim 1, wherein X is O and x is 1.
3. The compound of claim 2, wherein A1 is 1,3-phenylene.
4. The compound of claim 3, wherein A2 is phenyl, pyridyl, or naphthyl optionally substituted with halo, alkoxy, aryloxy, alkyl, cycloalkyl, aryl, or heteroaryl.
5. The compound of claim 4, wherein each of R1, R2, and R3 is H.
6. The compound of claim 5, wherein Y is 1,4-phenylene; and y is 0 or 1.
7. The compound of claim 1, wherein A1 is 1,3-phenylene; and A2 is phenyl, pyridyl, or naphthyl optionally substituted with halo, alkoxy, aryloxy, alkyl, cycloalkyl, aryl, or heteroaryl.
8. The compound of claim 7, wherein each of R1, R2, and R3 is H.
9. The compound of claim 1, wherein the compound is one of Compounds 1-26.
10. A method for treating hepatitis C virus infection, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):
Figure US20090176766A1-20090709-C00033
wherein
each of R1, R2, and R3, independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; or R1 and R2, together with the nitrogen atom to which they are bonded, are heterocycloalkyl; or R2 and R3, together with the two nitrogen atoms to which they are bonded and the carbon atom bonded to both of the two nitrogen atoms, are heterocycloalkyl;
A1 is arylene or heteroarylene;
A2 is aryl or heteroaryl;
each of X and Y, independently, is O, S, SO, SO2, N(Ra), C(RaRb), C(O), C(O)O, C(O)Na, NRaC(O)NRb, NRaC(S)NRb, NRaC(O)O, SO2NRa, alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, cycloalkenylene, heterocycloalkenylene, arylene, or heteroarylene, in which each of Ra and Rb, independently, is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Z is O or S;
each of m and n, independently, is 0, 1, 2, 3, 4, or 5;
p is 1, 2, or 3; and
each of x and y, independently, is 0 or 1.
11. The method of claim 10, wherein X is O and x is 1.
12. The method of claim 11, wherein A1 is 1,3-phenylene.
13. The method of claim 12, wherein A2 is phenyl, pyridyl, or naphthyl optionally substituted with halo, alkoxy, aryloxy, alkyl, cycloalkyl, aryl, or heteroaryl.
14. The method of claim 13, wherein each of R1, R2, and R3 is H.
15. The method of claim 14, wherein Y is 1,4-phenylene and; y is 0 or 1.
16. The method of claim 10, wherein A1 is 1,3-phenylene; and A2 is phenyl, pyridyl, or naphthyl optionally substituted with halo, alkoxy, aryloxy, alkyl, cycloalkyl, aryl, or heteroaryl.
17. The method of claim 16, wherein each of R1, R2, and R3 is H.
18. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
19. The composition of claim 18, wherein X is O and x is 1.
20. The composition of claim 19, wherein A1 is 1,3-phenylene.
21. The composition of claim 20, wherein A2 is phenyl, pyridyl, or naphthyl optionally substituted with halo, alkoxy, aryloxy, alkyl, cycloalkyl, aryl, or heteroaryl.
22. The composition of claim 21, wherein each of R1, R2, and R3 is H.
23. The composition of claim 22, wherein Y is 1,4-phenylene and; y is 0 or 1.
24. The composition of claim 19, wherein A1 is 1,3-phenylene; and A2 is phenyl, pyridyl, or naphthyl optionally substituted with halo, alkoxy, aryloxy, alkyl, cycloalkyl, aryl, or heteroaryl.
25. The composition of claim 24, wherein each of R1, R2, and R3 is H.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018509467A (en) * 2015-10-26 2018-04-05 ジァンスー カニオン パーマスーティカル カンパニー リミテッド Salt form, crystal form of 1,2,5-thiadiazolidine-1,1-dioxide and preparation method and intermediate thereof
WO2019183369A1 (en) * 2018-03-21 2019-09-26 University Of Miami Neurite outgrowth promoters and uses thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4221817A (en) * 1979-04-16 1980-09-09 American Cyanamid Company Method for the control of phytopathogenic fungi using phenylalkoxyphenylurea compounds
US6521614B1 (en) * 1996-04-17 2003-02-18 Bristol-Myers Squibb Pharma Company N-(amidinophenyl)cyclourea analogs as factor Xa inhibitors
US6696478B2 (en) * 1999-08-09 2004-02-24 Zhimin Lu Cancer treatment with Gö6976 and its related compounds
US20050032849A1 (en) * 2003-07-10 2005-02-10 Avinash Phadke Substituted arylthiourea derivatives useful as inhibitors of viral replication
US20050228013A1 (en) * 2004-01-06 2005-10-13 Andrew Thurkauf Azabenzofuran substituted thioureas; inhibitors of viral replication
US20060025416A1 (en) * 2004-05-18 2006-02-02 Avinash Phadke Substituted aryl acylthioureas and related compounds; inhibitors of viral replication
US7094807B2 (en) * 2002-11-19 2006-08-22 Achillion Pharmaceuticals, Inc. Substituted aryl thioureas and related compounds; inhibitors of viral replication
US7102007B2 (en) * 2000-12-21 2006-09-05 Hoffmann-La Roche Inc. Dihydroindole and tetrahydroquinoline derivatives

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE223408T1 (en) 1998-02-09 2002-09-15 Dimensional Pharm Inc HETEROARYL-AMIDINES, METHYLAMIDINES AND -GUANIDINES AS PROTEASE INHIBITORS, IN PARTICULAR AS UROKINASE INHIBITORS
FR2812633A1 (en) 2000-08-04 2002-02-08 Aventis Cropscience Sa PHENYL (THIO) UREA AND PHENYL (THIO) CARBAMATE FUNGICIDES DERIVATIVES
DE10257358A1 (en) * 2002-12-09 2004-07-08 Bayer Healthcare Ag Substituted pyrroles
WO2004096210A1 (en) 2003-05-01 2004-11-11 Glaxo Group Limited Acylated indoline and tetrahydroquinoline derivatives as hcv inhibitors
JP2005144790A (en) 2003-11-13 2005-06-09 Konica Minolta Medical & Graphic Inc Image forming method and production method of output matter for print proof reading
US20060100225A1 (en) 2004-03-23 2006-05-11 Xi Chen Heteroaryl guanidines; inhibitors of viral replication
AP2358A (en) 2005-05-09 2012-01-30 Achillion Pharmaceuticals Inc Thiazole compounds and methods of use.
US20070135368A1 (en) * 2005-12-09 2007-06-14 Knapp Pamela E Cell-to-cell transmission of siRNA induced gene silencing in mammalian cells

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4221817A (en) * 1979-04-16 1980-09-09 American Cyanamid Company Method for the control of phytopathogenic fungi using phenylalkoxyphenylurea compounds
US6521614B1 (en) * 1996-04-17 2003-02-18 Bristol-Myers Squibb Pharma Company N-(amidinophenyl)cyclourea analogs as factor Xa inhibitors
US6696478B2 (en) * 1999-08-09 2004-02-24 Zhimin Lu Cancer treatment with Gö6976 and its related compounds
US7102007B2 (en) * 2000-12-21 2006-09-05 Hoffmann-La Roche Inc. Dihydroindole and tetrahydroquinoline derivatives
US7094807B2 (en) * 2002-11-19 2006-08-22 Achillion Pharmaceuticals, Inc. Substituted aryl thioureas and related compounds; inhibitors of viral replication
US20050032849A1 (en) * 2003-07-10 2005-02-10 Avinash Phadke Substituted arylthiourea derivatives useful as inhibitors of viral replication
US20050228013A1 (en) * 2004-01-06 2005-10-13 Andrew Thurkauf Azabenzofuran substituted thioureas; inhibitors of viral replication
US20060025416A1 (en) * 2004-05-18 2006-02-02 Avinash Phadke Substituted aryl acylthioureas and related compounds; inhibitors of viral replication

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018509467A (en) * 2015-10-26 2018-04-05 ジァンスー カニオン パーマスーティカル カンパニー リミテッド Salt form, crystal form of 1,2,5-thiadiazolidine-1,1-dioxide and preparation method and intermediate thereof
WO2019183369A1 (en) * 2018-03-21 2019-09-26 University Of Miami Neurite outgrowth promoters and uses thereof
US11981660B2 (en) 2018-03-21 2024-05-14 University Of Miami Neurite outgrowth promoters and uses thereof

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